title: Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions.
abstract: Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe- mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.forename: Greet
authors.initials: G
authors.lastname: De Smet
authors.forename: Martina
authors.initials: M
authors.lastname: Gärtner
authors.forename: Magda
authors.initials: M
authors.lastname: De Smedt
authors.forename: Els
authors.initials: E
authors.lastname: Waegemans
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D029721:Drosophila Proteins; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C424126:DLL4 protein, human; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D016695:Glycosyltransferases; C498393:LFNG protein, human